Cannabis use is common among individuals with HIV/AIDS. Its medical use for HIV symptom management continues to gain acceptance and recent changes to state laws have made it increasingly easier for HIV-seropositive (HIV+) individuals to obtain cannabis. Although cannabis has therapeutic potential, its use is also known to cause neurocognitive deficits. This is of particular concern to individuals with HIV, who are already vulnerable to such impairments. Indeed, a substantial amount of research shows that various substances of abuse often compound HIV-associated neurocognitive deficits. Yet, despite its widespread use, the effects of cannabis in this population have been relatively unexplored. Little is known regarding the type and extent of neurocognitive impairments that cannabis use may confer to HIV+ individuals, their impact on important functional behaviors (e.g., medication management), or the underlying mechanisms. The proposed project will address these issues by first characterizing rigorously how cannabis use and HIV relate to neuropsychological functioning in a large cohort of 400 community-dwelling adults, stratified by HIV-serostatus and cannabis use. The second aim examines how cannabis use may adversely affect important functional real-world behaviors of HIV+ individuals. The final aim tests a theory-driven model that includes several mechanisms through which cannabis use may directly and indirectly influence neurocognitive functioning among HIV+ individuals. This model is based on strong preclinical evidence showing both immunosuppressive and anti-inflammatory effects of cannabinoids. Structural equation modeling will be used to test any direct effects that cannabis has on neurocognition, as well as any indirect effects that may be driven by its immunosupressive properties. The model will simultaneously examine if anti-inflammatory effects from cannabis are serving to mitigate neurocognitive deficits among those with HIV. The results of this proposal will yield a more complete understanding of how cannabis use influences neurocognition among HIV+ individuals. Our findings have the potential to improve the health and quality of life of HIV+ individuals, further neuroAIDS research, and inform healthcare decisions and policies regarding use of cannabis among individuals with HIV/AIDS. PUBLIC HEALTH RELEVANCE: This study will help us understand if cannabis use affects the neurocognitive functioning of HIV+ individuals and whether it impairs their ability to conduct important daily activities (e.g., managing medications and finances). It will also reveal if the effects of cannabis use on immune functioning and inflammatory processes are possible underlying mechanisms for its neurocognitive effects. The new information provided by our study has the potential to improve the health of individuals living with HIV/AIDS and may help policy makers and healthcare providers in deciding the role of cannabis in HIV/AIDS patient care.